Alterations in the intrauterine environment, such as altered maternal substrate utilization during pregnancy, is associated with poor fetal growth, postnatal catch up growth, and altered glucose and lipid metabolism, leading to Type 2 Diabetes Mellitus and obesity in adult life. Using a unique mouse model of high fat feeding during pregnancy and lactation we demonstrated that maternal "metabolic flexibility" is passed on to their offspring and that mothers with diminished metabolic flexibility programmed their offspring to manifest a thrifty phenotype, while mothers with increased metabolic flexibility programmed their offspring to manifest a lean phenotype. The central hypothesis of this proposal is that maternal "metabolic inflexibility" to burn fat in response to high fat feeding during pregnancy and lactation programs an epigenotype of "metabolic inflexibility" in their offspring. The SPECIFIC AIMS to address this hypothesis will: 1. define the liver and skeletal muscle epigenotypes of offspring "metabolic in/flexibility" programmed by maternal substrate utilization;2. evaluate the impact of altered maternal substrate utilization at critical periods of development on offspring "metabolic in/flexibility" and on their liver and skeletal muscle epigenotypes. We propose that the epigenotype of metabolic flexibility will show a more normal pattern of histone acetylation and DNA CpG methylation and that maternal metabolic flexibility during pregnancy and lactation programs an epigenotype of similar metabolic flexibility in their offspring. The major impact of these studies will be on pregnancies associated with low birth weight or very low birth weight, where the fetus is predisposed to the later development of metabolic disease. Our studies may encourage pregnant women to change their lifestyle and result in more healthful pregnancies. PUBLIC HEALTH RELEVANCE: The factors that mediate the interaction between the maternal diet, genes and the cellular memory (epigenome) of her offspring that influence disease susceptibility in later life are not fully understood. Using a mouse model, the effect of maternal high fat diet on the epigenome of the exposed offspring and its impact on the later development of metabolic diseases will be determined. Advances in this area from the proposed research studies will identify new therapeutic targets to improve human health.